Project 4

Structural studies on extracellular and cytosolic domains of aGPCR

Norbert Sträter & Torsten Schöneberg, Leipzig University

Team members
Björn Kieslich
Vera Lede

Project Description
Adhesion-G-Protein-coupled Receptors (aGPCR) are a large receptor family which has been only partially investigated so far concerning its biochemical, structural and functional properties. The aim of the project is to characterise the spatial structures of the receptors and their interactions with binding partners by X-ray structure analysis. Such studies are the basis to understand the molecular function of the receptors and for a structure-based development of potential drugs acting on these receptors. To this end, the receptors and single domains are expressed in three different expression systems: E. coli, HEK cells and insect cells. For structural and biophysical investigations milligram quantities of highly pure protein need to be prepared. The following processes in the mode of action of the receptors will be primarily studied: The binding of ligands to the extracellular binding domains and the conformational changes in the interaction of the binding domains and the GAIN domains induced thereby and, furthermore, the interaction between the GAIN domain and the transmembrane part, which is probably conserved in all aGPCR. Finally, the structures of the intracellular domains and their binding to the currently mainly unknown cytosolic interaction partners shall be studied.

Publications

Demberg LM, Winkler J, Wilde C, Simon KU, Schön J, Rothemund S, Schöneberg T, Prömel S, Liebscher I (2017) Activation of Adhesion G Protein-coupled Receptors: AGONIST SPECIFICITY OF STACHEL SEQUENCE-DERIVED PEPTIDES. J Biol Chem. 292:4383-4394. 

Araç D, Sträter N, Seiradake E (2016) Understanding the Structural Basis of Adhesion GPCR Functions. Handbook of Experimental Pharmacology 234:67-82. 

Fischer L, Wilde C, Schöneberg T, Liebscher I (2016) Functional relevance of naturally occurring mutations in adhesion G protein-coupled receptor ADGRD1 (GPR133). BMC Genomics 17:609. 

Kovacs P, Schöneberg T (2016) The Relevance of Genomic Signatures at Adhesion GPCR Loci in Humans. Handbook of Experimental Pharmacology 234:179-217. 

Wilde C, Fischer L, Lede V, Kirchberger J, Rothemund S, Schöneberg T, Liebscher I (2016). The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J. 30:666-73.  

Demberg LM, Rothemund S, Schöneberg T, and Liebscher I (2015) Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. Biochem Biophys Res Commun 464:743-747. 

Müller A, Winkler J, Fiedler F, Sastradihardja T, Binder C, Schnabel R, Kungel J, Rothemund S, Hennig C, Schöneberg T, Prömel S (2015) PLoS Genet 11(10):e1005624.

Petersen SC, Luo R, Liebscher I, Giera S, Jeong S-J, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, and Monk KR (2015) The Adhesion GPCR GPR126 Has Distinct, Domain-Dependent Functions in Schwann Cell Development Mediated by Interaction with Laminin-211. Neuron 85:755–769.

Schöneberg T, Liebscher I, Luo R, Monk KR, Piao X (2015) Tethered agonists: a new mechanism underlying adhesion G protein-coupled receptor activation. J Recept Signal Transduct Res. 35:220-3. 

Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, and Schiöth HB (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.

Liebscher I, Schön J, Petersen SC, Fischer L, Auerbach N, Demberg LM, Mogha A, Cöster M, Simon K-U, Rothemund S, Monk KR, and Schöneberg T (2014) A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133. Cell Reports 9:2018–2026.